Postprandial effects of cholecystokinin are mediated by brainstem PrRP neurons
Bibliographic record
Abstract
Cholecystokinin (CCK) is a gut-hormone, released from the I-cells of the small intestine, with an overarching role in postprandial metabolism. It induces satiation, regulates gastric motility and restrains potentially dangerous excursions in plasma glucose following the ingestion of a meal. CCK acts in a paracrine fashion by binding to CCK1 receptors on sensory vagal afferents, which in turn activate circuits in the brainstem dorsal vagal complex. Our lab has shown previously that central prolactin-releasing peptide (PrRP) regulates food intake and mediates CCK-induced satiety1-3. Furthermore, we have also found that central PrRP reduces gastric motility and plasma glucose, suggesting that it may have an all-encompassing role in mediating the actions of CCK. PrRP is expressed in three discrete areas in the brain: the nucleus of the solitary tract (NTS) and the ventrolateral medulla (VLM) in the brainstem; and dorsomedial nucleus of the hypothalamus (DMN). Using the Cre/loxP system, we genetically dissected the hypothalamic and brainstem neurocircuits by creating a murine knock out of PrRP where expression is selectively rescued in the brainstem alone. The knockout of PrRP (LSL-PrRP) was generated by inserting a loxSTOPlox codon between the PrRP promoter and coding sequence in mice. Immunohistochemistry confirmed the lack of PrRP expression in the brainstem and the hypothalamus. On normal chow, LSL-PrRP mice are significantly heavier than wild-type littermates by 12 weeks of age, and are particularly susceptible to diet-induced obesity, similar to PrRP-/- mice4. Intraperitoneal injection of CCK (10 mg kg-1) significantly decreased food intake in wild-type littermates under nocturnal feeding conditions. In contrast, CCK did not reduce food intake in LSL-PrRP animals. Unlike those in the DMN, PrRP neurons in the brainstem are noradrenergic and express tyrosine hydroxylase (TH). Expression of PrRP in the brainstem, but not the hypothalamus, was rescued by crossing LSL-PrRP mice with TH-Cre mice. This was confirmed by immunohistochemistry. Wild-type and TH-Cre x LSL-PrRP mice respond to intraperitoneal CCK, with a significant reduction in food intake under nocturnal feeding conditions. In contrast, CCK did not reduce food intake in their LSL-PrRP littermates. Therefore, rescue of PrRP in the brainstem alone protects against obesity and restores anorectic responses to CCK. We hypothesize that PrRP acts through its endogenous receptor, GPR10 to affect CCK-induced reductions in gastric motility and plasma glucose. Intracerebroventricular administration of PrRP suppresses the glucose excursion, following an oral glucose load, in wild-type but not GPR10-/- mice. Exogenous PrRP also decreases the rate of gastric emptying, an effect which is blocked with co-administration of a GPR10 receptor antagonist. Thus, PrRP is important in mediating the effects of CCK on inhibiting gastric emptying and food intake, and, may have indirect effects on glucose tolerance. This makes PrRP/GPR10 signaling an attractive anti-obesity candidate that warrants more attention in the understanding of the neural circuitry implicated energy balance. 1. Lawrence, C.B., Celsi, F., Brennand, J. & Luckman, S.M. Alternative role for prolactin-releasing peptide in the regulation of food intake. Nature neuroscience 3, 645-646 (2000). 2. Lawrence, C.B., Ellacott, K.L.J. & Luckman, S.M. PRL-releasing peptide reduces food intake and may mediate satiety signaling. Endocrinology 143, 360-367 (2002). 3. Bechtold, D.a. & Luckman, S.M. Prolactin-releasing Peptide mediates cholecystokinin-induced satiety in mice. Endocrinology 147, 4723-4729 (2006). 4. Takayanagi, Y., et al. Endogenous prolactin-releasing peptide regulates food intake in rodents. The Journal of clinical investigation 118, 4014-4024 (2008).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".